Almost all very low birth weight preterm infants require respiratory support (mechanical ventilation or CPAP) at birth, and up to 40% of these infants will develop bronchopulmonary dysplasia (BPD). Since BPD affects the smallest and most preterm infants, many of the infants surviving with BPD have neurodevelopmental disabilities and injuries to other organs. Lung inflammation and injury resulting from mechanical ventilation are central to the development of BPD. Prolonged mechanical ventilation has been linked to MRI changes and poor neurologic outcomes, and mechanical ventilation causes systemic changes in liver, brain inflammation and MRI changes in sheep. Recent trials of inhaled budesonide, budesonide mixed with surfactant, postnatal dexamethasone, and early postnatal low-dose hydrocortisone have all decreased the risk of BPD. However, concerns exist for systemic effects of steroids. Different postnatal steroids regimens have been associated with worse neurologic outcomes. The balance between a lung benefit and neurologic harm for these regimens needs to be determined before widespread use. Our preliminary data demonstrate systemic changes in the liver and brain with mechanical ventilation that can be altered by postnatal steroids. Using a preterm lamb models, we will evaluate lung and brain responses to mechanical ventilation and postnatal steroids, and identify possible toxic effects on the newborn. By combining antenatal exposures to corticosteroid and mechanical ventilation, we can determine interactions that could alter lung maturation and postnatal lung function. Results will be assessed using physiology, pathology, and advanced molecular techniques for the lung and brain. We will use mRNA sequencing to evaluate a wide range of potential injury pathways. We propose two specific aims to 1) define the role of clinically relevant steroids (dexamethasone, budesonide in surfactant, hydrocortisone) in mechanical ventilation and 2) interactions with antenatal corticosteroids and mechanical ventilation on brain injury. Our proposal is innovative because it uses unique preterm sheep models to evaluate the lung and brain effects of postnatal steroids in clinically relevant settings of lung injury and antenatal steroids. These exploratory studies fit well with the R21 mechanism and will provide important information for assisting clinical decisions in the NICU.